Heart Failure Paradox: Women Outlive Men Despite Less Effective Treatment

Reviewed by Giuseppe Biondi Zoccai and Emmanuel Androulakis

Heart failure continues to be a significant global health challenge, affecting more than 60 million people worldwide (1). Over the years, advances in medical and device therapy have dramatically improved survival for patients with heart failure. Despite these developments, long-term outcomes remain variable and are influenced by a complex interplay of patient-specific factors, including sex differences in pathophysiology and clinical presentation.

This background sets the stage for the recent study by Qui et al. (2) published in the European Journal of Preventive Cardiology, evaluating the long-term prognostic differences between men and women with heart failure. The findings of this large meta-analysis of 96 cohorts including 706,247 patients of who 43% were women, revealed that women tend to have better overall survival. Overall mortality in women was reduced compared to men (hazard ratio=0.83 [95% confidence interval: 0.80-0.85]) as was cardiac mortality (0.84 [0.79-0.89]). This held true even if women were generally treated less commonly with guideline-directed therapy. For instance, fewer women compared to men were on a renin-angiotensin-aldosterone inhibitor, beta-blocker or mineralocorticoid inhibitor. However, it is important to note that men had generally lower left ventricular ejection fraction (LVEF) compared to women.

These results emphasize the need to recognize and address sex-specific differences in disease mechanisms, treatment responses and outcomes. What remains to be explored, however, is whether these observed differences translate into actionable changes in clinical practice. Should guidelines advocate for sex-specific interventions or highlight targeted approaches for risk stratification in heart failure management? Are for example women benefiting equally from renin-angiotensin-aldosterone inhibition as men? Some data suggest they are not (3) therefore guidance will be well received on who is more likely to benefit. Similarly, SGLT2 inhibitors may be more effective in men than women (4). If this is indeed the case, would all women benefit from SGLT2 inhibitors, or can we identify a sub-group of women that are more likely to benefit? Moreover, the study raises questions about the role of healthcare disparities and their potential influence on these findings. Why are fewer women on full guideline-based therapy? Where is the bottleneck? Is this delayed diagnosis, medication accessibility, bias from the healthcare providers or financial insecurity? This is an important aspect highlighted that would need addressing to improve the health of any nation.

While the study offers valuable insights, some limitations should be considered, including its observational nature, potential residual confounding, and the variability in diagnostic criteria across the centres included. Nevertheless, these results highlight the importance of tailoring heart failure care to the needs of individual patients, considering both biological and sociodemographic factors.

The broader implications of these findings call for further research to deepen our understanding of sex differences in heart failure and highlight again that women are generally underrepresented in clinical trials. Moving forwards, it will be crucial to develop research and personalised strategies that optimise outcomes for all patients, regardless of sex. As the healthcare community strives for equity and excellence in care, studies like this pave the way for more refined and effective interventions that may also need to be sex-specific.